The goal of this research is to better understand the influence of sex-dependent factors on the development of alcoholism. The overarching hypothesis is that there are sex differences in the liability toward alcohol abuse. More specifically, we hypothesize that sex differences partially derive from the effects of gonadal hormones and heritable levels of b-endorphin to influence the neural and behavioral stress response and modify the pleasure derived from alcohol (EtOH) administration. In Specific Aim 1, we will use mouse models to characterize the role of male versus female gonadal hormones in the effects of stress on EtOH self-administration. Our hypothesis here is that stress will increase the self-administration of EtOH, dependent upon gonadal hormones, such that an ovariectomy of female mice will counter this effect and that castration of male mice will promote it. Specific Aim 2 will focus on the role of b-endorphin (b-E) and endogenous opioid peptide in the sex-dependent effect of stress on the self-administration of EtOH. As differences in coping behavior and vulnerability to stress have a biological basis in HPA axis function and are modulated by b-E, we will use transgenic mice deficient in the capacity to synthesize b-E to test the hypothesis that behavioral responses contributing to allostasis of the stress response (i.e., EtOH self-administration) will vary as a function of this peptide. Finally, Specific Aim 3 is to employ at lest a dozen undergraduates, including female and underrepresented minority students, to work with the principle investigator on these research projects in a highly mentored environment. As an HHMI Distinguished Mentor with an exemplary record of collaborating with undergraduate students in the laboratory, the PI has a longstanding commitment to the educational benefit that these hands-on skills provide to future neuroscientists.